thiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed via diet at doses of up to 100 and 4mg/kg, respectively, prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats are 19 and 1.5 times, respectively, the maximum recommended human dose on amg/m2 basis. (Calculations assume an oral dose of 25mg/day and a 60-kg patient.)
13.3 Developmental Toxicity
Studies with amlodipine:No evidence of teratogenicity or other embryo/fetal toxicity wasfound when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the maximum recommended human dose [MRHD] of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well controlled studies in pregnant women.
Studies with valsartan:No teratogenic effects were observed when valsartan was administeredto pregnant mice and rats at oral doses of up to 600 mg/kg/day and to pregnant rabbits at oral doses of up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, andlow body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits, respectively, are about 9, 6 and 0.1 times the MRHD of 320 mg/day on a mg/m2 basis. (Calculations based on a patient weight of 60 kg.)
Studies with hydrochlorothiazide:Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats are 608 and 405 times, respectively, the maximum recommended human dose on amg/m2 basis. (Calculations assume an oral dose of 25mg/day and a 60-kg patient.)
Studies with amlodipine and valsartan:In the oral embryo-fetal development study in rats using amlodipine besylate plus valsartan at doses equivalent to 5 mg/kg/day amlodipine plus 80 mg/kg/day valsartan, 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan, and 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse-effect level (NOAEL) for embryo- fetal effects was 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan. On a systemic exposure [AUC(0-∞ |
